Avvaru Stephen Paul, Noolvi Malleshappa N, Aminbhavi Tejraj M, Chkraborty Sudipta, Dash Ashutosh, Shukla Shyam S
Department of Pharmaceutical Chemistry, Shree Dhanvantary Pharmacy College, Kim, Surat, 394110, India.
Radiopharmaceuticals Division, Bhabha Atomic Research Centre, India.
Mini Rev Med Chem. 2018;18(7):609-621. doi: 10.2174/1389557517666171101100902.
Aromatase inhibitors are class of drugs that inhibit aromatase, a rate limiting enzyme in the biosynthesis of estrogens from their corresponding androgens. Estrogens play a vital role in the development and growth of breast tumors especially in postmenopausal women apart from their important functions in cell homeostasis. The reduction of estrogen physiological concentration through aromatase inhibition is one of the most important therapeutic strategies against this cancer type. The third-generation aromatase inhibitors are now used as first-line therapy in the treatment of early and metastatic breast cancer in postmenopausal women. However the quest for new class of drugs still stays indispensable to evade the danger of conceivable rising resistances to existing drugs, toxicity and unwanted side effects due to chronic treatment. The current review deals with recent advances in understanding of aromatase, its mechanism and research in the development of various novel chemotypes as aromatase inhibitors. The new challenges and the fast changing trends in bringing rational approach in aromatase inhibitors to a different level like research in dual/multiple target enzyme inhibition strategies, radiolabeling of aromatase inhibitors as theranostic agents; the development of new computational models for complete understanding of aromatase enzyme and its substrate/ligand interactions will bring in holistic approach to comprehensive inhibition of aromatase and other relevant enzymes for effective treatment and monitoring of postmenopausal breast cancer.
芳香化酶抑制剂是一类抑制芳香化酶的药物，芳香化酶是从相应雄激素生物合成雌激素过程中的一种限速酶。雌激素在乳腺肿瘤的发生和发展中起着至关重要的作用，尤其是在绝经后女性中，此外它在细胞内环境稳定中也具有重要功能。通过抑制芳香化酶来降低雌激素的生理浓度是对抗这种癌症类型的最重要治疗策略之一。第三代芳香化酶抑制剂现已被用作绝经后女性早期和转移性乳腺癌治疗的一线疗法。然而，为了规避对现有药物可能出现的耐药性增加、毒性以及长期治疗带来的不良副作用等风险，寻求新型药物仍然不可或缺。本综述探讨了在芳香化酶的认识方面的最新进展、其作用机制以及各种新型化学类型作为芳香化酶抑制剂的研发情况。在将芳香化酶抑制剂的合理方法提升到不同水平方面面临的新挑战和快速变化的趋势，如双靶点/多靶点酶抑制策略的研究、将芳香化酶抑制剂作为治疗诊断剂进行放射性标记；开发新的计算模型以全面了解芳香化酶及其底物/配体相互作用，将为全面抑制芳香化酶和其他相关酶以有效治疗和监测绝经后乳腺癌带来整体方法。
